Methods for the synthesis of amines such as ephedrine and intermediates

ABSTRACT

A method for the preparation of a compound of formula (VI): in which R 2  is an optionally substituted C1-C6 alkyl; R 4  is H, OH, an optionally substituted C1-C6 alkyl or an optionally substituted C1-C6 alkoxy; R 5  is an optionally substituted aryl, an optionally substituted aralkyl, or an optionally substituted alkyl; and R 5  is H or an optionally substituted C1-C6 alkyl; the method including the step of subjecting a ketone of formula (V) in which R 2 , R 4  and R 5  are as defined above, to reductive animation with an amine of formula R 3 NH 2  in which R 3  is an optionally substituted alkyl, and a reductant to form the compound of formula (VI), wherein the reaction is conducted in the presence of a supercritical fluid or a liquefied gas.

[0001] The present invention relates to new environments in which toconduct certain classes of chemical reactions. The present inventionparticularly relates to new methods and environments for the synthesisof useful pharmaceutical compounds such as ephedrine.

BACKGROUND OF THE INVENTION

[0002] A range of important classes of pharmaceutical compounds, foodadditives and other biologically active compounds are based on chiralalkyl amines. Such classes of compounds include the sympathomimeticamines, such as ephedrine (α-[1-(methylamino)ethyl]benzene-methanol).Many of these compounds are commercially important and are synthesisedfor use in pharmaceutical compositions and in other applications.

[0003] Physicochemical methods for production of enantiomerically purecompounds usually involve multi-step synthesis incorporating one or moresteps which are asymmetric, and laborious purification procedures. Suchmethods are not only tedious, but frequently provide relatively pooryields. Alternatively enantiomerically-pure starting materials can beused, together with enantioselective reaction steps; however, such purestarting materials are available only for a very limited number ofdesired compounds.

[0004] In recent years, intense efforts have been directed towardsdevelopment of methods which are highly selective, provide a good rateof transformation, and enable easy, non-chromatographic separation andpurification of the product. It has also been considered particularlydesirable for the reactions to be carried out in non-aqueous solvents,since these are particularly convenient for large scale reactions andpurifications.

[0005] Ephedrine (α-[1-(methylamino)ethyl]benzene-methanol), originallyisolated from plants of the genus Ephedra, occurs as thenaturally-occurring isomers l-ephedrine and d-pseudoephedrine, and otherpharmacologically active isomers include d-ephedrine andl-pseudoephedrine. These compounds are adrenergic sympathomimetic agentsand have antihistamine activity; l-ephedrine is widely used as abronchodilator, while d-pseudoephedrine is widely used as adecongestant. Compounds of these groups are present in a very wide rangeof prescription and over-the-counter pharmaceutical formulations.

[0006] The production of l-phenylacetylcarbinol, a precursor ofl-ephedrine, by catalysis using whole baker's yeast cells in aqueousmedium was one of the first microbial biotransformation processes to beused commercially (Neuberg and Hirsch, 1921; see also Hildebrandt andKlavehn, 1934). This reaction involves the yeast-induced condensation ofbenzaldehyde with acetyl-coenzyme A. The reaction has been widelyinvestigated, and has been shown to be mediated by the enzyme pyruvatedecarboxylase (Groger, Schmander and Mothes, 1966). It has also beenshown that the reaction has a relatively broad specificity for thesubstrate, enabling a variety of substituted aromatic aldehydes to beconverted to the corresponding substituted optically-activephenylacetylcarbinols (Long, James and Ward, 1989).

[0007] Although this yeast-catalysed system has been widely exploited,this has normally utilised aqueous systems, which are inconvenient forlarge-scale extraction and purification, which require organic solvents.Additionally, fermentation systems present the disadvantage thatpurification of the desired product can be difficult, and yields tend tobe low; while the yield and convenience of the reaction can be improvedby utilising immobilised cells, or cells which have been selected orgenetically, modified, this adds significantly to the cost of theprocess. The use of purified enzymes is normally prohibitivelyexpensive, and again without the use of immobilised enzymes the yieldstend to be low and purification difficult.

[0008] In our earlier International Application PCT/AU00/01543, weshowed that yeast-mediated acyloin condensation of benzaldehyde can beachieved in supercritical or liquefied carbon dioxide or in liquefiedpetroleum gas. This reaction results in superior conversion of thearomatic aldehydes to the desired carbinol when compared with thecorresponding reaction conducted in conventional organic solvents. In apreferred embodiment, yields of around 79% with the total absence ofside-products were obtained using the method of the invention.

[0009] Based on experiments with other ketones and aldehydes, it wasbelieved that reductive amination of the carbinol could not be conductedin any mediums other than conventional organic solvents. Accordingly,the difficulty still remained that the intermediate had to be convertedinto l-ephedrine using conventional techniques in conventional organicsolvents.

[0010] It has now surprisingly been found by the present applicant thatreductive amination of the ketone precursor for ephedrine can beconducted in the presence of supercritical fluids or liquefied gasessuch as supercritical carbon dioxide or liquefied petroleum gas. Thesereagents are especially advantageous to use as the reaction medium inlarge scale reactions since the purification and processing of theproducts is simpler than comparable reactions conducted in standardorganic or aqueous solvents.

[0011] Similarly, the applicant has found that particular ketoneprecursors for compounds structurally related to ephedrine can besubjected to reductive amination to form the target amines insupercritical fluids or liquefied gases.

[0012] Since carbon dioxide is non-toxic and can be readily recycled,this method avoids the problems associated with reactions involvingorganic solvents. Moreover, when combined with earlier reactions orprocesses conducted in the same solvent, the target compound can be madein a “one-pot” process, thereby further maximising possible yields andsimplifying large scale operations for the synthesis of the compound.

SUMMARY OF THE INVENTION

[0013] According to one aspect of the present invention there isprovided a method for the formation of an amine of formula (VI):

[0014] wherein R₂ is optionally substituted C1-C6 alkyl;

[0015] R₄ is H, OH, optionally substituted C1-C6 alkyl or optionallysubstituted C1-C6 alkoxy;

[0016] R₅ is optionally substituted aryl, optionally substitutedaralkyl, or optionally substituted alkyl; and

[0017] R₆ is H or an optionally substituted C1-C6 alkyl;

[0018] the method including the step of reacting a ketone of formula (V)

[0019] in which R₂, R₄ and R₅ are as defined above, with a primary amineof formula R₃NH₂ in which R₃ is an optionally substituted alkyl, and areductant, in the presence of a supercritical fluid or a liquefied gas,to form the amine of formula (VI).

[0020] This method may be represented by the following reaction scheme:

[0021] Preferably, the reductant is H₂ and the reduction is conducted inthe presence of a suitable catalyst (so that R₆ is R₃). However, anotheroption is to utilise a hydride reducing agent such as NaBH₄ or LiAlH₄.With the appropriate selection of the amine reagent II (ie R₃) andhydride reducing agent, the group R₃ which is initially present in theenamine intermediate formed is removed during the reduction step, sothat R₆ will be H. With the selection of other R₃ groups and appropriatehydride reducing agent, this does not occur, so that R₆ will be R₃. Thereducing reagent(s) can be added to the reaction mixture together withthe secondary amine of formula (II), or in a subsequent step.

[0022] According to one embodiment of the invention, the amine (VI) isselected from the group consisting of ephedrine (R₄=OH, R₅=phenyl,R₂=methyl, R₆=R₃ methyl), isoetharine (R₄=OH, R₅=3,4-dihydroxyphenyl,R₂=ethyl, R₆=R₃=isopropyl), ritodrine (R₄=OH, R₅=4-hydroxyphenyl,R₂=methyl, R₆=R₃=2-(4-hydroxyphenyl)ethyl), methamphetamine (R₄=H,R₅=phenyl, R₂=methyl, R₆=R₃=methyl), fenfluramine (R₄=H,R₅=3-trifluoromethylphenyl, R₂=methyl, R₆=R₃=ethyl) and propylhexedrine(R₄=H, R₅=cyclohexyl, R₂=methyl, R₆=R₃=methyl). These compounds arepreferably formed using hydrogen and a catalyst as the reductant,although they can be formed using a hydride reducing agent.

[0023] According to an alternative embodiment of the invention, theamine (VI) is selected from the group consisting of amphetamine,methoxamine, phenylpropanolamine, hydroxyamphetamine,ethylnorepinepherine and metaraminol. These compounds may be formedusing a hydride reducing agent as the reductant.

[0024] The reductive amination reaction involves the formation of animine intermediate prior to the reduction taking place. Accordingly, asecond aspect of the present invention provides a method for theformation of an imine of formula (III)

[0025] the method comprising reacting a ketone of formula (V) as definedabove with an amine of the formula R₃NH₂ in which R₃ is as definedabove, in the presence of a supercritical fluid or a liquefied gas.

[0026] In a preferred embodiment of the invention for the synthesis ofan amine of formula (VI) in which R₄ is OH, hereafter referred to ascompound (VIa):

[0027] the method involves the preliminary step of forming a ketone offormula (V) in which R₄ is OH (hereafter referred to as compound (Va)):

[0028] by subjecting an aldehyde of formula R₅—CHO to acyloincondensation mediated by yeast with a compound of formula (VIII):

[0029] in which R₂ is as defined above and R₇ is H or alkyl; to yieldthe ketone of formula (Va), wherein the acyloin condensation step isconducted in the presence of a supercritical fluid or a liquefied gas.

[0030] These steps are summarised in the following reaction scheme:

[0031] in which:

[0032] R₂, R₃, R₅, R₆ and R₇ are as defined above.

[0033] Preferably, the reaction is conducted without isolation orpurification of the compound of formula (Va). More preferably, thereactions to form the compound of formula (VIa) from the aldehyde R₅—CHOare conducted in one vessel.

[0034] Reduction can be effected by any suitable reducing agent.Accordingly, for example, the imine intermediate could be reduced byLiAlH₄ (in an appropriate supercritical fluid or liquefied gas medium,which would not be based on CO₂ due to possible reaction of CO₂ withthis reagent) to form a primary amine product. In one embodiment of theinvention hydrogen and an appropriate hydrogenation catalyst is used toconduct the reduction. This yields compounds of Formula (VI) in which R₆is the group R₃ which comes from the amine reagent R₃NH₂. Suitablehydrogenation catalysts include platinum and palladium. Full detailsconcerning appropriate reduction reactions and hydrogenation catalystsfor reducing the carbon-nitrogen double bond can be found in S. Patai,The Chemistry of the Carbon-Nitrogen double bond, Wiley, New York, 1970,pp276-293 and P. N. Rylander, Catalytic Hydrogenation over PlatinumMetals, Academic Press, New York, 1967, pp123-138.

[0035] In the situation where the reductive amination involveshydrogenation of the imine in the presence of a catalyst, it ispreferred that the yeast is recovered from the reaction vessel after theacyloin condensation step, and before the reductive amination, and thecatalyst is recovered after the reductive amination.

[0036] The amine reagent used in the reductive amination or in the imineformation reaction can be added in any convenient form appropriate forthe reaction medium. It may be in the form of a neat solid, liquid orgas, or as a solution in an appropriate solvent. In a preferredembodiment of the invention, it has been found that excellent conversionis obtained when the amine is added in an organic solvent, and thereaction is conducted in a liquefied gas. The organic solvent may inthis instance be the same as the liquefied gas.

[0037] In all of the broad processes described above, the supercriticalfluid may be any supercritical fluid that does not interfere with thereaction. The temperature of the reaction will depend on the propertiesof the supercritical fluid used and the reagents used in the fullreaction sequence. Accordingly, the reaction temperature might be anytemperature up to 200° C., preferably up to 50° C., as is appropriate tothe reaction. Similarly, the pressure will depend on the properties ofthe supercritical fluid, and might range from 500 psi (for low criticalpressure-supercritical fluids such as sulphur hexafluoride) up to 7000psi. The critical temperature and pressure of CO₂ are 31.1° C. and 1070psi, respectively. For a procedure that involves a yeast-mediatedreaction in the reaction scheme, we have found that carbon dioxide isparticularly suitable, as the reaction can be performed at a moderatelyelevated temperature, suitably between 33 to 42° C., preferably 35° C.At these temperatures, the corresponding pressure may range between 1070to 2500 psi or higher, preferably 1500 psi.

[0038] Other suitable supercritical fluids are as follows: Criticaltemperature Critical pressure Fluid (° C.) (psi) Ethane 32.4 707.8Nitrous oxide 36.6 1050 Xenon 16.7 847 Fluoroform (CHF₃) 26.3 705Monofluoromethane 42 812.2 Sulphur hexafluoride 45.7 545.3Chlorotrifluoromethane 29 561.3

[0039] It is to be noted that supercritical ammonia is not anappropriate supercritical fluid in which to conduct the reactions, sinceammonia may interfere with the reactions. In particular, ammonia mayinterfere with the imine formation or reductive amination.

[0040] When one of the processes described above is performed in thepresence of a supercritical fluid, the target compound can be recoveredby subjecting the reaction mixture to extraction with a supercriticalfluid or an organic solvent such as ethylacetate or diethylether.

[0041] Further information regarding equipment design and control andthe selection of suitable pressures and temperatures for certainsupercritical fluids can be found in Chemical Synthesis UsingSupercritical Fluids Edited by Philip G Jessop and Walter Leitner.

[0042] The liquefied gas may be carbon dioxide, a, hydrocarbon such asmethane, ethane, propane, butane, ethylene, or the like, or mixturesthereof. Liquefied petroleum gas may be used. Again, the reactiontemperature and pressure would be selected taking into account theproperties of the liquefied gas being used, and the properties ofreaction reagents.

[0043] Once the reaction has been completed in liquefied gas, the systemis de-gassed and the target compound can be extracted with asupercritical fluid, a liquefied gas or an organic solvent.

[0044] As regards the preferred process which involves the preliminarystep of a yeast mediated acyloin condensation reaction, it is noted thatany yeast capable of effecting the acyloin condensation reaction may beused. It is economically advantageous to use the cheapest yeastavailable, and ordinary baker's yeast, Saccharomyces, cerevisiae, ispreferred. Strains of yeast adapted to other purposes, including brewingyeast and wine or sherry yeasts could also be employed. Strainsspecifically adapted to a supercritical fluid environment or forenhanced acyloin condensation efficiency may be used; such strainsinclude conventionally-selected and genetically modified strains. Formaximum efficiency of reaction, it is advisable to present the maximumsurface area of yeast for contact with the reactants. This can beeffected by using “active” dried yeast, which is readily commerciallyavailable as “instant dry yeast”, and may be stored at room temperature.Alternatively, well-pulverised dry baker's yeast may be used. Otheryeasts, such as those described in U.S. Pat. No. 4,734,367, or fungisuch as those disclosed in Chenevert et al (1992) may also be used. Theperson skilled in the art will readily be able to test whether anyspecific organism will function for the purposes of the invention, usingthe methods described herein.

[0045] While the ratio of yeast to substrate will vary depending on theindividual system, and is readily determined experimentally usingroutine trial and error methods, we have found that for the conversionof benzaldehyde to phenylacetylcarbinol the optimum ratio is 4.2 gyeast/mmol-benzaldehyde; increasing the amount of yeast results in onlya small increase in conversion, and lower amounts of yeast provide lowerconversion.

[0046] Similarly, the optimum reaction time may readily be determined,and for the benzaldehyde-phenylacetyl-carbinol system we haveinvestigated reaction times from 3 to 24 hours. Reactions longer than 24hours do not lead to higher yields.

[0047] The supercritical fluid or liquefied gas used in the process canbe recycled. The yeast can be used for other purposes, for example inanimal feed, especially when this fluid or gas is carbon dioxide.

[0048] As used in the present application, the term “imine” refers toany compound containing a carbon to nitrogen double bond, and thereforethis term includes oximes, semicarbazones, and substituted orunsubstituted arylhydrazones (such as 2,4-dinitrophenylhydrazone).

[0049] The term “amine” is used herein in its broadest sense to refer toany compound containing a nitrogen atom. The term amine thereforeencompasses ammonia, primary, secondary and tertiary amines includingalkyl amines, hydroxyamines, alkoxy and aryloxy amines, alkenyl amines,alkynyl amines, amines with silicon-containging substituents such astrimethyl silane, nitrogen-containing heterocyclic compounds,heterocyclyl amines, alkylsulphonyl amines, arylsulphonyl amines, acylamines (ie amides), alkylthio amines, benzylthio amines, acylthioamines, amines with phosporous-containing substituents, semicarbazides,hydrazines and arylhydrazines, all of which may optionally besubstituted with one or more non-deleterious substituent.

[0050] Where it is stated that a group may be “substituted”, it is to beunderstood that the group may include one or more substituent selectedfrom alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl,haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy,haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroalkyl,nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino,alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino,diarylamino, benzylamino, dibenzylamino, acyl, alkenylacyl, alkynylacyl,arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy,arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino,haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy,carboaryloxy, mercapto, alkylthio, benzylthio, acylthio, andphosphorus-containing groups. Where appropriate, these groups may beprotected by suitable protecting groups.

[0051] Preferably, the or each substituent is selected from the groupconsisting of alkyl, aryl, halo; haloalkyl (including trihalomethyl, forone example), nitro, hydroxy, alkoxy, amino, carbonyl, thioxy andthioalkoxy.

[0052] The term “alkyl” used either alone or in a compound word such as“optionally substituted alkyl” or denotes straight chain, branched ormono- or poly-cyclic alkyl, preferably C₁₋₁₈ alkyl or cycloalkyl.Examples of straight chain and branched alkyl include methyl, ethyl,propyl, isopropyl, butyl, isbutyl, sec-butyl, tert-butyl, amyl, isoamyl,sec-amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl,5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl,4,4-dimetylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl,1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, nonyl,1-, 2-, 3-, 4-, 5-, 6- or 7-methyloctyl, 1-, 2-, 3-, 4- or5-ethylheptyl, 1-2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-and 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or4-propylheptyl, undecyl 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl,1-, 2-, 3-, 4-, 5-6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl,1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-5-, 6-,7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or4-butyloctyl, 1-2-pentylheptyl and the like. Examples of cyclic alkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl and cyclodecyl and the like. In some instancesthe alkyl group is indicated to be of a particular size or length by useof the expression “C1-Cx alkyl”. The number of carbon atoms denoted isto be taken to refer to the number of carbon atoms in the alkyl group tothe exclusion of any further substituents.

[0053] In a preferred embodiment the compound of formula (VIII) (anα-keto carboxylic acid or carboxylic acid ester) is pyruvic acid or apyruvate buffer (ie R₂ is CH₃).

[0054] In a preferred embodiment of the invention, the compound offormula (VII) is substituted or unsubstituted benzaldehyde, the compoundof formula (V) is substituted, or unsubstituted phenylacetylcarbinol,and the compound of formula (VI) is ephedrine or a derivative thereof.

[0055] In a particularly preferred embodiment of the invention, there isprovided a process for forming ephedrine or a derivative thereof from asubstituted or unsubstituted benzaldehyde, the process being inaccordance with reaction scheme E:

[0056] wherein R₇ is as defined above.

[0057] It will be clearly understood that the benzaldehyde (IX), thepyruvic acid (VIII), or both may optionally be substituted, and thatpyruvate, for example sodium pyruvate, may be used as an alternative topyruvic acid. As a further alternative, a precursor of pyruvic acidwhich can be converted in situ to pyruvic acid may be used, for example,lactic acid, unless the supercritical fluid or liquefied gas is carbondioxide. Aromatic aldehydes substituted with alkyl, aryl, halo, nitro,hydroxy, alkoxy, amino, carbonyl, thioxy or thioalkoxy groups orcomposites of these groups may also be used instead of benzaldehyde inthis preferred embodiment of the invention.

[0058] For either sodium pyruvate or pyruvic acid, the pH of thepyruvate/citrate buffer solution is preferably between 5 and 6, morepreferably pH 6. Between 0.6 and 1.2 ml buffer/g of yeast shouldpreferably be used for optimal results.

[0059] For the avoidance of any doubt, it is to be understood that whenthe compound being subjected to reduction includes other functionalgroups that can be reduced by the subject reducing agent, thecorresponding target compound (defined or described by words or chemicalstructure) should be interpreted to include corresponding compoundsincluding reduced functional groups in place of the original functionalgroups.

[0060] According to the present invention there is also provided acompound prepared by any one of the processes described above.

EXAMPLES

[0061] The invention will now be described in further detail by way ofreference only to the following non-limiting examples.

Example 1 Reaction in Supercritical Carbon Dioxide Using LiquidMethylamine

[0062] Phenylacetylcarbinol (0.2 g, 1.3 mmol), palladium catalyst (0.05g) and liquid methylamine (3 mls) were placed into a 250 ml stainlesssteel pressure vessel. The vessel was pressurised up to 400 psi withhydrogen gas and then up to a total of 1500 psi by pumping dried liquidcarbon dioxide into the vessel. The vessel was then stirred in a 35° C.water bath for 24 h. After 24 h, the reaction vessel was cooled to roomtemperature and slowly de-gassed. The vessel contents and residue waswashed three times with diethyl ether and filtered. Gas chromatographyanalysis revealed 78% conversion of phenylacetylcarbinol (PAC) toephedrine.

Example 2 Reaction in Supercritical Carbon Dioxide Using Methylamine inTHF

[0063] Phenylacetylcarbinol (0.2 g, 1.3 mmol), palladium catalyst (0.05g) and 5 fold excess of 2.0M methylamine in THF (3.125 mls, 6.45 mmol)were placed into a 250 ml stainless steel pressure vessel. The vesselwas pressurised up to 400 psi with hydrogen gas and then up to a totalof 1500 psi by pumping dried liquid carbon dioxide into the vessel. Thevessel was then stirred in a 35° C. water bath for 24 h. After 24 h, thereaction vessel was cooled to room temperature and slowly de-gassed. Thevessel contents and residue was washed three times with diethyl etherand filtered. Gas chromatography analysis revealed 46% conversion ofphenylacetylcarbinol (PAC) to ephedrine.

Example 3 Reaction in Supercritical Carbon Dioxide Using GaseousMethylamine

[0064] Phenylacetylcarbinol (0.2 g, 1.3 mmol), palladium catalyst (0.05g) were placed into a 250 ml stainless steel pressure vessel. Anhydrousgaseous methylamine was vented into the vessel to a pressure ofapproximately 100 psi. The vessel was then pressurised up to 400 psiwith hydrogen gas and up to a final pressure of 1500 psi by pumpingdried liquid carbon dioxide into the vessel. The vessel was then stirredin a 35° C. water bath for 24 h. After 24 h, the reaction vessel wascooled to room temperature and slowly de-gassed. The vessel contents andresidue was washed three times with diethyl ether and filtered. Gaschromatography analysis revealed 32% conversion of phenylacetylcarbinol(PAC) to ephedrine.

Example 4 Reaction in Liquid Carbon Dioxide Using Liquid Methylamine

[0065] Phenylacetylcarbinol (0.2 g, 1.3 mmol), palladium catalyst (0.05g), liquid methylamine (3 mls) were placed into a 250 ml stainless steelpressure vessel. The vessel was pressurised up to 400 psi with hydrogengas and then up to a total of 1500 psi by pumping dried liquid carbondioxide into the vessel. The vessel was then stirred at room temperaturefor 24 h. After 24 h, the reaction vessel was slowly de-gassed. Thevessel contents and residue was washed three times with diethyl etherand filtered. Gas chromatography analysis revealed 63% conversion ofphenylacetylcarbinol (PAC) to ephedrine.

Example 5 Reaction in Liquid Carbon Dioxide Using Methylamine in THF

[0066] Phenylacetylcarbinol (0.2 g, 1.3 mmol), palladium catalyst (0.05g) and 5 fold excess of 2.0M methylamine in THF (3.125 mls, 6.45 mmol)were placed into a 250 ml stainless steel pressure vessel. The vesselwas pressurised up to 400 psi with hydrogen gas and then up to a totalof 1500 psi by pumping dried liquid carbon dioxide into the vessel. Thevessel was then stirred at room temperature for 24 h. After 24 h, thereaction vessel was slowly de-gassed. The vessel contents and residuewas washed three times with diethyl ether and filtered. Gaschromatography analysis revealed 97% conversion of phenylacetylcarbinol(PAC) to ephedrine.

Example 6 Combined Yeast-Mediated Acyloin Condensation of Benzaldehydeand Reductive Amination to Form Ephedrine

[0067] Benzaldehyde (0.137 g, 1.3 mmol), sodium pyruvate (2.168 g, 19.7mmol), pH 6 citrate buffer (5.4 ml) and yeast (5.4 g) were placed into a250 ml stainless steel pressure vessel. This vessel was pressurised to1500 psi by pumping dried liquid carbon dioxide into the vessel. Thevessel was then stirred in a 35° C. water bath for 24 h. After 24 h, thereaction vessel was cooled to room temperature and slowly de-gassed.

[0068] Phenylacetylcarbinol (0.2 g, 1.3 mmol), palladium catalyst (0.05g) and 5 fold excess of 2.0M methylamine in THF (3.125 mls, 6.45 mmol)was then placed into the stainless steel pressure vessel. The vessel waspressurised up to 400 psi with hydrogen gas and then up to a total of1500 psi by pumping dried liquid carbon dioxide into the vessel. Thevessel was then stirred in a 35° C. water bath for 24 h. After 24 h, thereaction vessel was cooled to room temperature and slowly de-gassed. Thevessel contents and residue was washed three times with diethyl etherand filtered. Gas chromatography analysis revealed 60% conversion ofphenylacetylcarbinol (PAC) to ephedrine.

[0069] It will be understood by persons skilled in the art that variousmodifications may be made to the embodiments and examples describedabove without departing from the scope of the invention.

1. A method for the preparation of a compound of

formula (VI): in which R₂ is an optionally substituted C1-C6 alkyl; R₄is H, OH, an optionally substituted C1-C6 alkyl or an optionallysubstituted C1-C6 alkoxy; R₅ is an optionally substituted aryl, anoptionally substituted aralkyl, or an optionally substituted alkyl; andR₆ is H or an optionally substituted C1-C6 alkyl; the method includingsubjecting a ketone of

formula (V) in which R₂, R₄ and R₅ are as defined above, to reductiveamination with an amine of formula R₃NH₂ in which R₃ is an optionallysubstituted alkyl; and a reductant to form the compound of formula (VI),wherein the reaction is conducted in the presence of a supercriticalfluid or a liquefied gas.
 2. The method according to claim 1, whereinthe reductant is hydrogen and the reduction is conducted in the presenceof a catalyst.
 3. The method according to claim 2, wherein the catalystis platinum or palladium.
 4. The method according to claim 1, whereinthe reductant is a hydride reducing agent.
 5. The method according toclaim 1, wherein the compound of formula (VI) is selected from the groupconsisting of ephedrine (R₄=OH, R₅=phenyl, R₂=methyl, R₆=R₃=methyl),isoetharine (R₄=OH, R₅=3, 4-dihydroxyphenyl, R₂=ethyl, R₆=R₃=isopropyl),ritodrine (R₄=OH, R₅=4-hydroxyphenyl, R₂=methyl,R₆=R₃=2-(4-hydroxyphenyl) ethyl), methamphetamine (4=H, R₅=phenyl,R₂=methyl, R₆=R₃=methyl), fenfluramine (R₄=H,R₅=3-trifluoromethylphenyl, R₂=methyl, R₆=R₃=ethyl) and propylhexadrine(R₄=H, R₅=cyclohexyl, R₂=methyl, R₆=R₃=methyl).
 6. The method accordingto claim 1, wherein the amine (VI) is selected from the group consistingof amphetamine, methoxamine, phenylpropanolamine, hydroxyamphetamine,ethylnorepinepherine and metaraminol.
 7. The method according to claim1, wherein the reaction temperature is 200° C. or less.
 8. The methodaccording to claim 7, wherein the reaction temperature is 50° C. orless.
 9. The method according to claim 1, wherein the reaction isconducted at a pressure of between 500 psi and 7000 psi.
 10. The methodaccording to claim 1, wherein the supercritical fluid is selected fromthe group consisting of carbon dioxide, ethane, nitrous oxide, xenon,fluoroform (CHF3), monofluoromethane, sulphur hexafluoride andchlorotrifluoromethane.
 11. The method as claimed in claim 10,comprising recovering the compound of formula (VI) by subjecting thereaction mixture to extraction with a supercritical fluid or an organicsolvent.
 12. The method as claimed in claim 1, wherein the reductiveamination is conducted in a liquefied gas selected from the groupconsisting of liquefied carbon dioxide or a liquefied hydrocarbon gas.13. The method as claimed in claim 12, comprising de-gassing the vesselin which the reductive amination was conducted after completion of thereaction, and extracting the compound of formula (VI) with asupercritical fluid, a liquefied gas or an organic solvent.
 14. Themethod as claimed in claim 12, wherein the reductive amination isconducted in liquid carbon dioxide at a pressure of between 1070 to 2500psi.
 15. The method according to claim 12, wherein the amine R₃NH₂ isadded to the reaction in an organic solvent.
 16. The method as claimedin claim 1, comprising recycling the supercritical fluid or liquefiedgas.
 17. The method as claimed in claim 1, wherein the substituent R₄ inthe compound of formula (VI) is OH, so that the product of the reductiveamination is a compound of formula (VIa):


18. The method as claimed in claim 17, wherein the method for formingthe compound of formula (VIa) includes: forming a ketone of formula (V)in which R₄ is OH (hereafter referred to as compound (Va)):

by subjecting an aldehyde of formula R₅—CHO to acyloin condensationmediated by yeast with a compound of formula (VIII):

in which R₂ is as defined above and R₇ is H or alkyl; to yield theketone of formula (Va), wherein the acyloin condensation step isconducted in the presence of a supercritical fluid or a liquefied gas.19. The method as claimed in claim 18, wherein the yeast isSaccharomyces cerevisiae.
 20. The method as claimed in claim 18, whereinR₅—CHO is benzaldehyde (R₅ is phenyl) and R₂ is methyl, and the yeast isadded in an amount of about 4.2 g yeast/mmol benzaldehyde.
 21. Themethod as claimed in claim 20, wherein the acyloin condensation reactionis conducted over a period of between 3 and 24 hours.
 22. A method forthe preparation of an imine of formula (III)

the method comprising reacting a ketone of formula (V) as defined inclaim 1 with an amine of the formula R₃NH₂ in which R₃ is as defined inclaim 1, in the presence of a supercritical fluid or a liquefied gas.